Ovarian cancer (OVCA) is the leading cause of gynecologic cancer mortality and the sixth most common cancer diagnosed in women in the United States. Advanced-stage epithelial OVCA is highly heterogeneous at a clinical, biologic, and genetic level, but patients are currently treated in a uniform fashion with cytoreductive surgery and platinum/taxane-based combination chemotherapy. Unfortunately, most patients ultimately succumb to persistent or recurrent platinum-resistant disease (Gadducci A, et al. Gynecol Oncol 68: 150-5, 1998; McGuire W P, et al. N Engl J Med 334: 1-6, 1996). Currently, efforts to develop therapeutic agents with greater efficacy against platinum-resistant disease are limited because of incomplete understanding of the molecular determinants of OVCA drug response.
Gemcitabine (2′,2′-difluorodeoxycytidine), a synthetic nucleoside analog of cytidine, is frequently used as a second-line therapy for patients with relapsed OVCA (Ozols R F. Semin Oncol 28: 18-24, 2001). As a pyrimidine analogue, gemcitabine replaces the nucleic acid cytidine during DNA replication, blocking processing and chain elongation by the DNA polymerase complex, resulting in G1 arrest and a subsequent cytostatic effect. Additionally, the gemcitabine triphosphate metabolite is incorporated into RNA, thus inhibiting RNA synthesis (Mackey J R, et al. Cancer Res 58: 4349-57, 1998). Gemcitabine efficacy has been evaluated extensively both in vitro and in vivo against OVCA (Distefano M, et al. Oncol Res 12: 355-9, 2000; Peters G J, et al. Semin Oncol 22: 72-9, 1995; Ruiz van Haperen V W, et al. Biochem Pharmacol 48: 1327-39, 1994; Ruiz van Haperen V W, et al. Cancer Res 54: 4138-43, 1994). Gemcitabine has demonstrated single-agent activity against OVCA cell lines (Ruiz van Haperen V W, et al. Semin Oncol 22: 35-41, 1995) and synergistic activity with several other antineoplastic agents, including platinum compounds, topotecan, and etoposide (van Moorsel C J, et al. Semin Oncol 24: S7-17-S7-23, 1997). In animal tumor models, the gemcitabine effect has been shown to be schedule-dependent, and continuous infusions over 24 hours appear to enhance gemcitabine cytotoxicity (Braakhuis B J, et al. Semin Oncol 22: 42-6, 1995). Phase II and III studies of gemcitabine (800-1250 mg/m2/week) in patients with recurrent OVCA have demonstrated response rates up to 19% (Friedlander M, et al. Ann Oncol 9: 1343-5, 1998; Lund B, et al. J Natl Cancer Inst 86: 1530-3, 1994; Markman M, et al. Gynecol Oncol 90: 593-6, 2003). Despite such data, the molecular determinants of gemcitabine activity remain to be fully elucidated.
Tailored strategies are needed that stratify patients based on their molecular fingerprints, e.g., those with the “highest risk” disease, those who may benefit from additional pathway-targeted therapy added to standard of care cytotoxic regimens, and those who may (or may not) benefit from aggressive surgical interventions.